1. Field of the Invention
The present invention relates to a novel method for producing nucleoside derivatives, more precisely to a novel method for producing nucleoside derivatives including 9-(2,3-dideoxy-2-fluoro-.beta.-D-threo-pentofuranosyl)adenine (hereinafter referred to as "FddA") and its related compounds which are useful as anti-viral agents, to novel intermediates in the method, and to a novel method for producing the intermediates.
2. Description of the Related Art
It is reported that 9-(2,3-dideoxy-2-fluoro-.beta.-D-threo-pentofuranosyl) adenine (FddA) has a strong anti-viral activity against human immunodeficiency virus (HIV) and is greatly effective for treatment of acquired immune deficiency syndrome (AIDS) (see V. E. Marquetz, et al., Biochem. Pharmacol., (36) page 2719, 1987; P. Herdewijn, et al., J. Med. Chem., (30), page 2131, 1987), and many clinical tests using it for the treatment of AIDS and AIDS-related complications (ARC) are being made at present. Recently, in addition, reported are FddA derivatives as modified at the nucleic acid base site to improve their potency (see C. K. Chu, et al., J. Med. Chem., (37), page 821, 1994; J. S. Driscoll, et al., J. Med. Chem., (39), page 1619, 1996; C. K. Chu, et al., J. Med. Chem., (39), page 4676, 1996).
The most direct method for producing FddA and its related compounds comprises substituting a substrate, of which the 3'-position in the saccharide moiety is deoxylated, at its 2'-position (see P. Herdewijn, et al., J. Med. Chem., (30), page 2131, 1987; V. E. Marquez, et al., J. Med. Chem., (33), page 978, 1990; H. Shiragami, et al., Nucleosides & Nucleotides, (11), page 391, 1992). However, the yield in the conventional methods is extremely low or is not higher than 10% and the reagent, diethylaminosulfer trifuluoride (DAST), is not available in industrial amount, and therefore the methods could not be used for industrial production of FddA and its related compounds.
1. Problems to be Solved by the Invention PA0 and then subjecting the resulting compound (3) to substitution with a group Z at its 6-halogen atom to give the compound (8), PA0 or subjecting the compound (3) to deprotection at the 5'-position to convert the same into 5'-deprotected derivative (8').
In the course of the completion to the present invention, the above and following problems in the related art have been also found by the present inventors.
Given the situation as above, it is desired to develop an inexpensive method for producing nucleoside derivatives including 9-(2,3-dideoxy-2-fluoro-.beta.-D-threo-pentofuranosyl)adenine (FddA) and its related compounds, in a simplified manner and at a high yield, in particular, an economical and industrial method for producing those nucleoside derivatives that comprises substituting a substrate, of which the 3'-position of the saccharide moiety is deoxylated, at its 2'-position at a high yield. Accordingly, the subject matter in the art is to provide such an excellent production method.
The object of the present invention is to develop an advantageous method for producing the nucleoside derivatives noted above, especially those having anti-viral activity, and to provide intermediates in the method and also a simple method for producing the intermediates.